Will Aseptic Connectors Make Production Outside of the Cleanroom Possible?

With the growing acceptance of single-use systems in parenteral manufacturing, there is a need to be able to connect plastic subsystems to each other and to permanent stainless equipment. Manufacturing flexibility achieved through the adoption of single-use components is an important consideration in improving production economics. Aseptic connectors are one piece of equipment that can impact production costs and adaptability.

“Connectors are a small component within the manufacturing system, but they are critical to achieving overall system integrity and performance, and if implemented appropriately, they can have a real impact on the efficiency and cost-effectiveness of drug production,” notes John Boehm, business unit manager for bioprocessing at Colder Products Company. Recently, they have become even more important as closed single-use systems have become more prevalent. With a move to create complete unit operations with single-use technology, these systems often increase in size and complexity, which creates new challenges for packaging, sterilizing, and handlings such large systems. The response has been to build and irradiate smaller subsystems. Of course, these subsystems then must be integrated within a manufacturing facility, which is enabled by sterile connectors.

The need to produce a large number of smaller-volume parenteral drugs is also driving demand for connector technology. “Drug manufacturers are no longer building large stainless facilities, but [are using] smaller, single-use or hybrid sites located around the world that can meet the needs of the local population. Being able to make a number of different products at such a site is very important and requires that the production equipment be both reliable and flexible,” Boehm explains.

Robust and easy to use
As a company focused solely on connection technology, Colder observed these trends and realized that the industry needed a more robust aseptic connector that was easy to use and didn’t require any external clamps or other parts to ensure sterility. The company’s first solution offering under the AseptiQuick brand was a gendered connector (male and female halves that mated together to form the seal) that is assembled by clicking together the two halves, followed by removal of a sterile membrane (by pulling a tab on the connector) and then twisting of a lock ring to increase the pressure rating from 30 to 60 psi.

Although these gendered connectors are robust and easy to use, Colder recognized that having gendered parts meant the system did not offer maximum flexibility, according to Boehm, because system designers and process engineers still had to be concerned about the gender of the parts when determining how to connect different systems together.

Adding flexibility
The next-generation AseptiQuik G connectors being introduced by Colder address this problem and incorporate additional features (see Figure 1). Genderless connectors simplify system integration and process design, says Boehm. “If a genderless connector is specified, then there is no concern for whether the connector on other subsystems is male or female. Customers see these types of connectors as building blocks for their single-use systems, and in some cases have already been doing beta-testing of the new designs. They have determined that costs will be driven down as a result of the increased flexibility they provide.”
Boehm also believes that with common connectors it will be possible to change the industry norm of creating new customized system configurations with each new project to a new paradigm of implementing standardized subsystems as building blocks. A parenteral manufacturer can develop and use a catalog of subassemblies from which it will be possible to construct customized and complex manufacturing systems. “Standardizing subsystems, which is made much easier and efficient with the use of genderless connectors, will mean that drug manufacturers won’t need to have to wait 12 or more weeks for custom production equipment to be built. That means faster time to market and reduced costs.”

Seal design
Perhaps the most important feature of the company’s new genderless format is a patent-pending seal design, which provides the consistent reliability and robust performance required of an aseptic connector, according to Boehm. “The performance of our wide-format silicon seal allowed us to simplify the connection process, which limits the risk of operator error.” A connection can be made simply by 1) unsnapping and flipping down the protective pull tab covers on each connector half, 2) aligning the connector halves, sliding them together, and independently squeezing each side of the connector until an audible click is heard, and3) snapping the pull tabs together and pulling the membranes from the connector to complete the connection (see Figure 2).

“A significant difference with our new design compared to others on the market is that a sterile seal rated to 60 psi is achieved when the connectors are first clicked together; no additional fixtures or clamps are needed prior to or following membrane removal in order to ensure that the sterile barrier is maintained,” Boehm adds.

One advantage of such sterile connectors is that connections do not need to be made in a laminar flow hood like conventional connectors do. Because the connection can be made anywhere in the cleanroom, there is no need for permanent hoods with extra long tubing runs or space for mobile hoods to be brought in to the production area.

This space savings further maximizes the advantages of single-use systems for biopharmaceutical manufacturers, according to Boehm. He gives as an example using cell-culture processes. With the increased titers now possible, several smaller 1000-L single-use bioreactors that fit into a room can replace large 10,000-L stainless-steel reactors that must be installed in a multistory space. The use of genderless, aseptic connectors thus further reduces the space requirements as well as reducing the facility construction time.

Moving outside the cleanroom
Boehm notes that some customers are testing the performance of Colder’s aseptic connectors outside of the cleanroom. The belief is that if the connectors meet specifications outside of the cleanroom, then they clearly will provide the needed performance inside the cleanroom. “More interesting, though, is the longer-term goal of convincing regulators that it is possible to achieve an aseptic environment outside of the cleanroom with closed systems. If this goal can be achieved, then some processes that currently must be run in a cleanroom could be carried out in a declassified production environment, which could lead to tremendous cost savings,” Boehm observes. “Cleanrooms are very expensive to build. Reducing the amount of required cleanroom space would lead to significant savings in capital investment and much shorter lead times.”

Boehm also notes that during the last pandemic threat, governments realized the criticality of gaining timely access to vaccines and are interested in developing smaller vaccine production facilities that can serve local populations, which could be possible if the production of such vaccines could be carried out without a cleanroom. Highly robust, sterile connectors may assist in making such a scenario plausible.

What’s next?
Colder’s sterile connector offering has increased to include solutions ranging from 1/8- to 1-inch flow, with both gendered or genderless options depending on the manufacturers’ preference. “We will continue to focus on the development of new connection technologies that address the evolving needs of parenteral manufacturers, whether for smaller-scale clinical runs or full-scale commercial production, and whether the manufacturer’s strategy is for completely disposable technology or hybrid facilities,” states Boehm.